Malaria is the most frequent parasitic infectious disease in the world. It is caused by a eukaryotic microorganism of the Plasmodium genus which is transmitted through biting by a female mosquito (Anopheles). Several species of Plasmodium can infect human beings, but Plasmodium falciparum is the most frequent and most pathogenic species and the species that is responsible for deadly cases. Once introduced in the blood, the parasite infects hepatic cells, in which it proliferates, before circulating again in the blood and invading red blood cells (erythrocytes). Malaria affects about a hundred countries in the world, in particular poor tropical regions of Africa, Asia and South America, Africa being by far the most affected continent. The World Health Organization estimates that malaria is responsible for 225 millions of cases of fever and approximately one million deaths annually (World Malaria Report, WHO, 2010). Currently available means of fighting against malaria infection include anti-malaria drugs (in particular chloroquine and quinine) and action against mosquitoes, vectors of the parasite. However, the situation is all the more worrisome that for several years, the parasites have developed increased resistance to drugs and mosquitoes have developed resistance to insecticide. Today, there are no vaccines available against malaria.
Malaria affects mainly children of less than 5 years of age and pregnant women, in particular primigravidae (i.e., women who are pregnant for the first time). Pregnant women are particularly vulnerable because the placenta constitutes a target where parasites can accumulate. In pregnant women, malaria infection can cause a large variety of damaging effects: spontaneous abortion, early delivery, low weight at birth, congenital transmission, and neonatal death. In the African regions where malaria is endemic, 3 to 5% of newborn deaths can be imputed to pregnancy-associated malaria. Furthermore, it is also a real danger for the mother who can suffer from sometimes severe, or even deadly, anaemia.
Today prevention of malaria in pregnant women is achieved by preventive administration of sulfadoxine/pyrimethamine (Cot et al., Br. Med. Bull., 2003, 67: 137-148). However, this intermittent treatment cannot provide a prevention against malaria during the entire pregnancy; firstly because administration of the drugs only takes place from the 20th week of pregnancy (the teratogenic risks during embryogenesis being too high); secondly because the treatment involves two curative doses of sulfadoxine/pyrimethamine administered at one month interval, which only provides partial medicinal protection; and thirdly because the efficacy of sulfadoxine/pyrimethamine is very strongly decreasing in all malaria endemic zones due to a rise in parasite resistance (Cot et al., Am. J. Trop. Med. Hyg., 1998, 59: 813-822; WHO/HTM/MAL/2005.1103. Geneva: World Health Organization; ter Kuile et al., JAMA, 2007, 297: 2603-2616; Mockenhaupt et al., J. Infect. Dis., 2008, 198: 1545-1549; Briand et al., J. Infect. Dis., 2009, 991-1001; Harrington et al., Proc. Natl. Acad. Sci. USA, 2009, 106: 9027-9032). Drugs are currently tested in this context, and numerous efforts are focused toward the development of a vaccine against placental malaria. The possibility of vaccinating pregnant women or prepubertal girls would offer several obvious advantages over the sulfadoxine/pyrimethamine treatment, since the preventive protection would be temporally extended, and probably of higher quality.
One of the contemplated vaccinal strategies to fight against pregnancy-associated malaria is to re-create the natural protective immunity. Indeed, the clinical severity of malaria caused by Plasmodium falciparum is, at least partly, linked to alterations undergone by infected erythrocytes. These alterations are induced by proteins of the parasite that are exported to the surface of erythrocytes during the phase of development in blood. Some of these surface proteins of the PfEMP1 (Plasmodium falciparum Erythrocyte Membrane Protein 1) family, confer novel cytoadherence properties to infected erythrocytes. The infected erythrocytes bind to the internal walls of blood vessels, thereby becoming unavailable for transport towards purging organs of the immune system, whose role is to destroy cells recognized as abnormal. In pregnancy-associated malaria, infected erythrocytes adhere to chondroitin sulfate A (CSA), a sulfated glycosaminoglycan present in the placenta. After several pregnancies, women acquire protective antibodies that block this adherence. One vaccinal strategy is to re-create this protective immunity by blocking the attachment of infected erythrocytes to the placenta.
The VAR2CSA protein, one of the members of the PfEMP1 family, is currently the object of numerous research projects with the goal of developing a vaccine specifically adapted to pregnant women (Tuikue Ndam et al., J. Infect. Dis., 2005, 192: 331-335; Chia et al., J. Infect. Dis., 2005, 192: 1284-1293; Tuikue Ndam et al., J. Infect. Dis., 2006, 193: 713-720; Dahlback et al., PLoS Pathogens, 2006, 2: 1069-1082; Badaut et al., Mol. Biochem. Parasitol., 2007, 15: 89-99; Khattab et al., Parasitol. Res., 2007, 101: 767-774; Guitard et al., Malaria J., 2008, 11: 7-10; Guitard et al., Malaria J., 2010, 9: 165; Gangnard et al., Mol. Biochem. Parasitol., 2010, 173: 115-122; Gnidehou et al., Mol. Biochem. Parasitol., 2010, 5(10): e13105). Although these studies are rendered difficult by VAR2CSA polymorphism, Phase I trials are nevertheless contemplated. Furthermore, the full-length extracellular domain of this protein has recently been expressed in a heterologous system (Srivastava et al., Proc. Natl. Acad. Sci. USA, 2010, 107: 4884-4889; Khunrae et al., J. Mol. Biol., 2010, 397: 826-834), and antibodies induced against this construct showed a very high anti-adhesion IgG titer. However, technological constraints in the optimal production of such a large antigen question the use of full length VAR2CSA in vaccine development. Furthermore, the development of new vaccinal approaches will have to take into account the numerous immunodominant epitopes that do no induce “antiadherent” antibodies.
Therefore, it appears to be crucial to continue exploring and developing new strategies to fight and prevent pregnancy-associated malaria.